Heart failure (HF) affects >4.7 million people (US), with >500,000 new cases/yr. Causes of HF include coronary artery disease, diabetes mellitus, hypertension, valvular disease, viral myocarditis, and genetic/metabolic disorders. With each event, sequellae that are initially compensatory, result in distinct types of left ventricular (LV) myocardial remodeling. Since the pathogenic mechanisms leading to HF display important differences, the goal of this SCCOR proposal is to unravel mechanisms of LV remodeling in three disparate forms of heart disease--volume overload of mitral regurgitation (MR), primary aldosteronism, and diabetic cardiomyopathy--that are resistant to standard medical therapy. We will study the role of sympathetic nervous system- and mast cell-mediated matrix metalloproteinase activation and extracellular matrix degradation in progressive adverse LV remodeling and failure in patients with MR and dog models of this disease. We will study the role of dietary salt status, inflammation, and mast cells in aldosterone-induced myocardial fibrosis and LV remodeling in patients and/or in genetic models of mast cell deficiency. We will determine whether AT1 receptor blockade and xanthine oxdidase inhibition will attenuate LV remodeling and dysfunction in the area opposite the infarct in diabetic patients. This will also study diabetic rats following a hemodynamic stress that duplicates the type of geometric remodeling in the area remote to the myocardial infarction in humans. Administrative will assure an effective integration of scientific and clinical functions. Bioanalysis will provide consistent and responsive analytical data that supports the hypothesis-testing. Imaging will provide in vivo measurements of LV function and geometry for SCCOR. Biostatistics will support with respect to data management and analysis of results. In aggregate, we will identify common and unique pathogenic mechanisms for HF and will employ novel therapeutic strategies in patients based on insights gained from both clinical investigation and the study of clinically relevant animal models.